SARS-COV-2 infection causes massive lung-cell senescence

INTRODUCTION: Older age is an important risk factor for severe COVID-19 disease. Understanding the biological mechanisms that link aging to the pathogenesis of COVID-19 is essential for developing of therapeutic strategies. We hypothesized that cell senescence, a basic aging process that plays a pivotal role in lung diseases, is involved in the pathogenesis of COVID-19 including the development of long-lasting lung alterations. METHODS: To evaluate the impact of SARS-CoV-2 infection on cell senescence, we (1) analyzed publicly available datasets of scRNA-seq performed in BALF cells from patients with moderate or severe/critical COVID-19; (2) investigated lung samples from cynomolgus macaques infected with 10(6) pfu of a SARS-CoV-2 clinical isolate. Two macaques were sacrificed at 4 days post-infection (dpi.) and two others at 30 dpi. RESULTS: In BALF obtained within 10 days after symptom onset, the expression of several senescence markers, i.e., CDKN2A, CDKN1A (encoding p21), uPAR, CXCL8, IGFBP3, and GDF15 was significantly increased in epithelial cells in BALF from patients with severe COVID-19, suggesting that lung-cell senescence induction was contemporary of viral detection. Next, we investigated macaques at 4 and 30 dpi, corresponding respectively to the viral load peak and to the absence of detectable viral RNA in BALF (1). Immunohistochemical analysis revealed numerous SARS-CoV-2 antigen-stained cells, also co-stained for senescence markers p16- and p21. The lungs at 30 dpi no longer contained the consolidated parenchymal areas seen at 4 dpi but showed extensive lung parenchyma remodelling, with thickening of the alveoli and pulmonary vessel walls and abundant extracellular matrix deposits as assessed by collagen staining. These lesions were accompanied with massive accumulation of p16- and p21-positive cells, mostly pneumocytes II and ECs. Of note, p16 staining of most ECs was seen in pulmonary vessels, notably those occluded by thrombosis and showing intraluminal vWF staining. Cells stained for p16 were alsostained for the DNA damage markers γ-H2AX protein and p53-binding protein [1]. CONCLUSIONS: Our data constitute the first evidence of temporal and topographic relations between senescent-cell accumulation and pulmonary lesions induced by SARS-CoV-2 infection.